CD23 Regulates monocyte activation through a novel interaction with the adhesion molecules CD11b-CD18 and CD11c-CD18

Treschow

The Journal of Immunology

et al. 2003

192

190

Since the basic mechanisms behind the beneficial effects of IFN-β in multiple sclerosis (MS) patients are still obscure, here we have investigated the effects of IFN-β gene disruption on the commonly used animal model for MS, experimental autoimmune encephalomyelitis (EAE). We show that IFN-β knockout (KO) mice are more susceptible to EAE than their wild-type (wt) littermates; they develop more severe and chronic neurological symptoms with more extensive CNS inflammation and demyelination. However, there was no discrepancy observed between wt and KO mice regarding the capacity of T cells to proliferate or produce IFN-γ in response to recall Ag. Consequently, we addressed the effect of IFN-β on encephalitogenic T cell development and the disease initiation phase by passive transfer of autoreactive T cells from KO or wt littermates to both groups of mice. Interestingly, IFN-β KO mice acquired a higher incidence and augmented EAE regardless of the source of T cells. This shows that the anti-inflammatory effect of endogenous IFN-β is predominantly exerted on the effector phase of the disease. Histopathological investigations of CNS in the effector phase revealed an extensive microglia activation and TNF-α production in IFN-β KO mice; this was virtually absent in wt littermates. This coincided with an increase in effector functions of T cells in IFN-β KO mice, as measured by IFN-γ and IL-4 production. We suggest that lack of endogenous IFN-β in CNS leads to augmented microglia activation, resulting in a sustained inflammation, cytokine production, and tissue damage with consequent chronic neurological deficits.

Section: Discussionmentioning

confidence: 99%

IFN-β Gene Deletion Leads to Augmented and Chronic Demyelinating Experimental Autoimmune Encephalomyelitis

Treschow

The Journal of Immunology

et al. 2003

192

190

“…CD23 appears to mediate various pathogenic functions in IgE-mediated immunity including antigen focusing and presentation, regulating IgE synthesis, promoting T-and B-cell differentiation and growth and mediating the production of proinflammatory cytokines. [1][2][3][4][5][6][7][8] CD23 is a single-chain glycoprotein with an apparent molecular weight of 45 kDa. It is widely distributed on a variety of human cells 9 and can be cleaved into soluble CD23 fragments, which contribute to its diverse immune activities.…”

Section: Introductionmentioning

confidence: 99%

Polymorphism R62W results in resistance of CD23 to enzymatic cleavage in cultured cells

McFall

2007

Genes Immun

A nonsynonymous single nucleotide polymorphism (SNP) of the low-affinity IgE receptor (FceRII/CD23) gene resulting in an arginine to tryptophan exchange at amino-acid position 62 (R62W) has been associated with enhanced T-cell responses to antigen in allergic subjects. To explore the mechanism, a CD23(a) cDNA was cloned into the plasmid pCMVScript-CD23a-C with a C allele (R62). The pCMVScript-CD23a-T with T (W62) was produced using a site-directed mutagenesis approach. The pCMVScript-CD23a-C only (CC), mixture of pCMVScript-CD23a-T and pCMVSCript-CD23a-C (CT) and pCMVScript-CD23a-T only (TT) plasmids were transfected in Cos-7 cells at equivalence in transfection efficiency. No soluble CD23 was released from TT transfectants whereas a higher level of soluble CD23 was detected in CC than in CT transfectants. Human leukocyte elastase (HLE), cathepsin G, the dust mite allergen Der p I and ADAM 33 (A disintegrin and metalloproteinase) were found to cleave membrane CD23 in CC but not in TT transfectants, implying the resistance of CD23 to enzymatic cleavage associated with T mutant. Addition of tunicamycin resulted in the resistance of CD23 to Der p I mediated cleavage in CC but no change in TT transfectants. These results indicate that R62W influences the stability of membrane CD23 molecules due to possibly diminished N-glycosylation.

Journal of Biological Chemistry

“…This interaction mediates most of the CD23 activities (24 -26). CD23 has also been shown to regulate monocyte activation through an interaction with CD11b and CD11c (27), providing a new role of CD23 in inflammation (28).…”

mentioning

confidence: 99%

Binding of Anti-CD23 Monoclonal Antibody to the Leucine Zipper Motif of FcεRII/CD23 on B Cell Membrane Promotes Its Proteolytic Cleavage

Munoz

Brignone

Grenier-Brossette³

et al. 1998

Self Cite

In the present study we have compared the binding of two monoclonal antibodies to CD23, EBVCS1 and mAb25, which recognize the stalk and the lectin domain, respectively, on the CD23 molecule. At 4°C, EBVCS1 binds to about 10% of the receptors recognized by mAb25 on the B cell surface. At 37°C, whereas mAb25 reaches its maximal binding within a few seconds, EB-VCS1 requires 60 min to bind to the same extent. Stabilization of the oligomeric structure of CD23 with IgE strongly affects in a dose-dependent fashion the number of binding sites seen by EBVCS1 but not the t 1/2 to reach them, suggesting that EBVCS1 binds to the coiled coil region through an allosteric mechanism. EBVCS1 rapidly down-modulates the membrane CD23 expression with a coincident increase of CD23-soluble fragments in the culture medium, an effect that is inhibited by IgE. In contrast, mAb25, as well as IgE, protects CD23 from proteolytic cleavage and stimulates its endocytosis. These results suggest that EBVCS1 unravels the coiled coil structure of CD23, rendering it more susceptible to proteolytic attack. This supports the oligomeric model proposed previously (Gould, H., Sutton, B., Edmeades, R., and Beavil, A. (1991) Monogr. Allergy 29, 28 -49). The biological significance of these observations is discussed.